In the United States, two million individuals are legally blind and ten million more visually impaired from age-related macular degeneration (AMD). In the next decade, the incidence of this condition is expected to double. Currently, treatment is aimed toward limiting disease progression using dietary supplements and laser therapies. The long range goal associated with this research program is to better understand the genetic variation that underlies the condition in order to identify those at risk of the disease, provide insight into the molecular pathophysiology of AMD and establish prevention strategies and novel treatments. The objective of this particular renewal application is to continue and further our work to identify the genes involved in the development of AMD using extended families. Our central hypothesis remains that multiple genes are involved in determining disease susceptibility. We will be guided by our data from the first five years of investigation in which genetic linkage studies involving over one thousand individuals from more than one hundred extended families have identified several potential susceptibility loci and implicated the gene, hemicentin-1, in the pathogenesis of the condition. We propose to continue to test the hypothesis by pursuing the following specific aims: 1) collect and genotype additional subjects in order to expand previously ascertained families and add new large pedigrees; 2) undertake statistical analyses to identify and refine potential disease loci, to include a) parametric and nonparametric methods, b) sample stratification, and c) quantitative trait locus; and 3) find and identify AMD susceptibility genes by a) positional candidate gene association analyses of our pedigrees, b) positional candidate gene association analysis of our case-control cohorts, and c) identification of genes involved in epistatic interactions. We remain convinced that our approach is innovative because of our unique resource of extended families with this late-onset disease and significant because, based on the data collected to date, this study will continue to advance understanding of the genetics of age-related macular degeneration, the foremost cause of blindness in the elderly.